Long-Term FVIII Expression with Reduced Bleeding Following Gene Transfer for Hemophilia A: Follow-up on the Dirloctocogene Samoparvovec Phase I/II Trial

Introduction Hemophilia A (HA) is managed with factor (F)VIII replacement, or non-factor replacement therapy such as emicizumab. More recently, gene therapies have been under investigation for HA. These use a modified viral vector to deliver a functional FVIII gene to liver cells, aiming to safely provide long-term, stable FVIII expression to prevent bleeding. Dirloctocogene samoparvovec (SPK-8011), an investigational gene therapy, uses a modified adeno-associated viral vector designed to achieve clinically meaningful and sustained FVIII expression at the lowest possible dose. The ongoing Phase I/II trial (NCT03003533/NCT03432520) is evaluating the safety and efficacy of dirloctocogene samoparvovec, assessed by FVIII activity levels and patient-reported bleeding events. Method This open-label, multicenter, non-randomized trial enrolled participants into four dose cohorts, receiving a single intravenous dose ([ Fig. 1 ]). Fig. 1 Study design: a Phase I/II, open-label, multicenter, non-randomized trial Results At data cut-off (Oct 4, 2022), 24 participants were included across dosing cohorts. Median observation time was 191 (range: 2–285) weeks. Thirteen participants (54.2%) experienced 28 adverse events (AEs) related to dirloctocogene samoparvovec, including one serious AE, a Grade 2 alanine transaminase (ALT, a liver enzyme) elevation resulting in elective hospitalization for intravenous corticosteroid administration. Eight participants (33.3%) experienced 26 immunomodulatory therapy-related AEs. No FVIII inhibitors or thrombotic events were reported. Fourteen participants had transient ALT elevations per CTCAE Grade 1–3, with these being Grade 1 in 12/14 participants. Among 18 participants with≥1 year of follow-up, 16 showed sustained FVIII activity, with most in the mild HA range, and two lost FVIII expression within the first year following a presumed capsid immune response. These two participants were not included in efficacy analyses. In participants previously using prophylaxis (n=17) who received dirloctocogene samoparvovec, mean all-bleeds annualized bleeding rate (ABR) was reduced by 82% (95% confidence interval [CI]: 55–93%): ABR of 6.88 (95% CI: 4.17–11.37) pre-vector infusion versus 1.21 (0.55–2.66) post infusion. In participants previously using on-demand treatment (n=5), there was a 99% reduction (95% CI: 98–100%) in all-bleeds ABR: 27.17 (95% CI: 18.46–39.98) pre-vector infusion versus 0.23 (0.13–0.42) post infusion. Median annualized FVIII infusion rates (AIRs) starting 28 days post-vector infusion were 0.3 (interquartile range: 0.0–1.4) versus 85.5 (40.0–104.0) pre infusion. Conclusion With up to 5 years of follow-up (range: 2–285 weeks), a dirloctocogene samoparvovec infusion in participants with HA resulted in sustained year-to-year FVIII expression and clinically meaningful ABR and AIR reductions. No major safety signals were reported, indicating dirloctocogene samoparvovec was well tolerated. Publication History Article published online: 26 February 2024 © 2024. Thieme. All rights reserved. Georg Thieme Verlag Rüdigerstraße 14, 70469 Stuttgart, Germany

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